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Page 1 of 51
PRODUCT MONOGRAPH
Pr LAMISIL*
(terbinafine hydrochloride)
250 mg tablets (expressed as base)
topical cream 1% w/w (10 mg/g)
topical spray solution 1% w/w (10 mg/g)
Antifungal Agent
Novartis Pharmaceuticals Canada Inc. Date of Revision: April 8, 2013
Dorval, Quebec
H9S 1A9
Control No. 161170
* LAMISIL is a Registered Trademark
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3 SUMMARY PRODUCT INFORMATION ....................................................................... 3
INDICATIONS AND CLINICAL USE ............................................................................. 3
ACTION AND CLINICAL PHARMACOLOGY ........................................................... 18
STORAGE AND STABILITY ......................................................................................... 20
DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................ 20
PART II: SCIENTIFIC INFORMATION .............................................................................. 21 PHARMACEUTICAL INFORMATION ......................................................................... 21
PART III: CONSUMER INFORMATION ............................................................................. 47
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Pr LAMISIL*
(terbinafine hydrochloride)
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form / Strength Clinically Relevant Non-medicinal
Ingredients
Oral Tablets 250 mg terbinafine (as
terbinafine hydrochloride)
carboxymethyl starch
(For a complete listing see Dosage Forms,
Composition and Packaging)
Topical topical cream 1%
terbinafine hydrochloride 1% w/w
(10 mg/g)
(For a complete listing see Dosage Forms,
Composition and Packaging)
Topical topical spray solution 1%
terbinafine hydrochloride 1% w/w
(10 mg/g)
(For a complete listing see Dosage Forms,
Composition and Packaging)
INDICATIONS AND CLINICAL USE
LAMISIL* (terbinafine) is indicated in the treatment of fungal infections of the skin and nails caused
by dermatophytes such as Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T.
violaceum), Microsporum canis, Epidermophyton floccosum and yeasts of the genus Candida (eg. C.
albicans), as well as Malassezia furfur.
Oral LAMISIL*
Oral LAMISIL* is indicated in the treatment of onychomycosis (fungal infection of the nail) caused
by dermatophyte fungi.
Prior to initiating treatment with LAMISIL* Tablets, appropriate nail or skin specimens should be
obtained for laboratory testing (KOH preparation, fungal culture, or nail biopsy) in order to confirm
the diagnosis of onychomycosis or dermatomycosis.
Oral LAMISIL* may be considered for the treatment of severe tineal skin infections (tinea corporis,
tinea cruris and tinea pedis) which have been unresponsive to topical treatment.
Note: Oral LAMISIL* is not effective in pityriasis versicolor.
Topical LAMISIL*
Page 4 of 51
Cream
LAMISIL* cream is indicated in the treatment of fungal infections of the skin caused by
dermatophytes such as trichophyton, as well as yeast infections of the skin, principally those caused
by the genus Candida (e.g. Candida albicans).
LAMISIL* cream is also indicated in the treatment of pityriasis (tinea) versicolor due to Malassezia
furfur.
Spray
LAMISIL* spray is indicated in the treatment of fungal infections of the skin caused by
dermatophytes such as trichophyton.
LAMISIL* spray is also indicated in the treatment of pityriasis (tinea) versicolor due to Malassezia
furfur.
Note: Topical LAMISIL* is not effective in onychomycosis.
CONTRAINDICATIONS
LAMISIL* (terbinafine) is contraindicated in patients with a known hypersensitivity to terbinafine or
to any of the excipients of LAMISIL* or component of the container. (see DOSAGE FORMS,
COMPOSITION and PACKAGING)
WARNINGS AND PRECAUTIONS
Oral LAMISIL*
Serious Warnings and Precautions
Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of
LAMISIL* (terbinafine) Tablets for the treatment of onychomycosis and dermatomycosis in
individuals with and without pre-existing liver disease.
In the majority of liver cases reported in association with LAMISIL* use, the patients had serious
underlying systemic conditions and an uncertain causal association with LAMISIL*. The severity of
hepatic events and/or their outcome may be worse in patients with active or chronic liver disease.
Treatment with LAMISIL* Tablets should be discontinued if biochemical or clinical evidence of liver
injury develops.
Hepatic
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LAMISIL* (terbinafine) tablets are not recommended for patients with chronic or active hepatic
disease. Before prescribing LAMISIL* Tablets, liver function tests should be performed since
hepatotoxicity may occur in patients with and without pre-existing liver disease. Therefore periodic
monitoring (after 4-6 weeks of treatment) of liver function tests is recommended. LAMISIL* should
be immediately discontinued in case of elevation of liver function tests. Patients prescribed
LAMISIL* Tablets should be warned to report immediately to their physician any symptoms of
persistent nausea, decreased appetite, fatigue, vomiting, right upper abdominal pain or jaundice, dark
urine or pale feces. Patients with these symptoms should discontinue taking oral terbinafine, and the
patient’s hepatic function should be immediately evaluated.
Renal
The pharmacokinetics of LAMISIL* have been investigated in patients with renal impairment
(creatinine clearance 50 mL/ min); based on this study the use of LAMISIL* in renally impaired
patients is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
Metabolism
In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6 metabolism. Therefore,
patients receiving concomitant treatment with drugs predominantly metabolized by this enzyme, e.g.
certain members of the following drug classes, tricyclic antidepressants (TCAs), -blockers, selective
serotonine reuptake inhibitors (SSRIs), antiarrhythmics class 1A, 1B and 1C and monoamine oxidase
inhibitors (MAO-Is) Type B, should be followed up, if the co-administered drug has a narrow
therapeutic window (see DRUG INTERACTIONS).
Skin
Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with
eosinophilia and systemic symptoms) have been very rarely reported in patients taking LAMISIL*
tablets. If progressive skin rash occurs, treatment with LAMISIL* tablets should be discontinued.
Terbinafine should be used with caution in patients with pre-existing psoriasis or lupus erythematosus
as precipitation and exacerbation of psoriasis and cutaneous and systemic lupus erythematosus have
been reported in a postmarketing setting.
Ophthalmologic
Changes in the ocular lens and retina have been reported following the use of LAMISIL* Tablets in
controlled trials. The changes noted were non-specific and the significance of these changes is
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unknown.
Immune
Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical
trials. The clinical significance of this observation is unknown. However, in patients with known or
suspected immunodeficiency, physicians should consider monitoring complete blood counts in
individuals using LAMISIL* therapy for greater than six weeks.
Lupus erythematosus:
During post-marketing experience, precipitation and exacerbation of cutaneous and systemic lupus
erythematosus have been reported infrequently in patients taking LAMISIL*. LAMISIL* therapy
should be discontinued in patients with clinical signs and symptoms suggestive of lupus
erythematosus.
Hematologic
Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia)
have been reported in patients treated with LAMISIL* tablets. Etiology of any blood dyscrasias that
occur in patients treated with LAMISIL* tablets should be evaluated and consideration should be
given for a possible change in medication regimen, including discontinuation of treatment with
LAMISIL* tablets.
Neurologic, Special Senses
Sensory disturbances
Disturbances of visual, auditory and tactile senses have been reported (see ADVERSE REACTIONS).
If visual or hearing disturbances occur, LAMISIL* Tablets should be discontinued.
Taste Disturbance Including Loss of Taste
Taste disturbance, including taste loss, has been reported with the use of LAMISIL* Tablets. It can be
severe enough to result in decreased food intake, weight loss, and depressive symptoms. Taste
disturbance usually resolves within several weeks after discontinuation of treatment.
Isolated cases of prolonged taste disturbances have also been reported. If symptoms of a taste
disturbance occur, LAMISIL* Tablets should be discontinued.
Smell Disturbance Including Loss of Smell
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Smell disturbance, including loss of smell, has been reported with the use of LAMISIL* Tablets.
Smell disturbance may resolve after discontinuation of treatment, but may be prolonged (greater than
one year), or may be permanent. If symptoms of a smell disturbance occur, LAMISIL* Tablets should
be discontinued.
Psychiatric
Anxiety and depressive symptoms
Anxiety and depressive symptoms have occurred during postmarketing use of terbinafine secondary to
taste disturbances, as well as independent of taste disturbances. If depressive symptoms occur,
LAMISIL* Tablets should be discontinued.
Carcinogenesis and Mutagenesis
An increase in liver tumors was observed in male rats at the highest dose level (69 mg/kg) during a
life-time (123 weeks) carcinogenicity study. The changes included increased enzyme activity,
peroxisome proliferation and altered triglyceride metabolism. The changes have been shown to be
species specific since they were not seen in mice or monkeys.
Topical LAMISIL*
LAMISIL* cream and spray are for external use only. LAMISIL* topical formulations may be
irritating to the eyes. Contact with the eyes should be avoided. LAMISIL* spray should not be used
on the face.
In the case of accidental ocular contact, the eyes should be rinsed thoroughly with running water and
patients should consult a physician if any symptoms persist. In case of accidental inhalation, patients
should be advised to consult a physician if any symptoms develop and persist.
LAMISIL* spray should be used with caution in patients with lesions where alcohol could be
irritating.
Local skin reactions
LAMISIL* Cream contains cetyl alcohol and stearyl alcohol which may cause local skin reactions
(e.g contact dermatitis).
LAMISIL* Spray Solution contains propylene glycol which may cause skin irritation.
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General:
Special Populations
Women of child-bearing potential: Some cases of menstrual irregularities have been reported in
patients taking LAMISIL* tablets concomitantly with oral contraceptives, although the incidence of
these disorders remains within the background incidence of patients taking oral contraceptives alone. There are no data to suggest special recommendations for women of child-bearing potential.
Pregnant Women: Animal fetal toxicity studies did not reveal any teratogenic or embryofetotoxic
potential of terbinafine. However, there is only very limited documented clinical experience with
LAMISIL* (terbinafine) in pregnant women; therefore, unless the potential benefits outweigh any
potential risks, oral LAMISIL* or LAMISIL* cream should not be used during pregnancy.
Nursing Women: Terbinafine is excreted in breast milk; therefore mothers receiving oral treatment
with LAMISIL* should not breast feed. However, with LAMISIL* cream and spray treatment, the
small amounts absorbed through the skin are unlikely to affect the infant. Nursing mothers should
NOT apply LAMISIL* topical formulations to the breast. In addition, infants must not come into
contact with any treated skin area, including the breasts.
Fertility: No effect of terbinafine on fertility has been seen in animal studies (see section
TOXICOLOGY) and there are no data to suggest an effect on fertility in humans.
Geriatrics: Plasma concentrations and drug half-life appear to be slightly higher in elderly patients
than in the general population. In addition, the incidence of all adverse events in a Post Marketing
Surveillance study appeared to be slightly higher in the elderly at normal adult doses; however, the
overall rate of adverse events possibly or probably related to terbinafine did not appear to be different
compared to the general population. When prescribing tablets for patients in this age group, the
possibility of pre-existing impairment of liver or kidney function should be considered (see
PHARMACOKINETICS - Oral LAMISIL*).
Pediatrics: The safety and efficacy of LAMISIL* have not been established in pediatric patients.
LAMISIL* should be kept out of the reach of children.
Occupational Hazards
Effects on ability to drive and use machines
No studies on the effects of LAMISIL* tablets treatment on the ability to drive and use machines have
been performed. Patients who experience dizziness as an undesirable effect should avoid driving
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vehicles or using machines. ADVERSE REACTIONS
Adverse Drug Reaction Overview
Because clinical trials are conducted under very specific conditions, the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and should
not be compared to the rates in the clinical trials of another drug. Adverse drug reaction
information from clinical trials is useful for identifying drug-related adverse events and for
approximating rates.
Frequency estimate: very common 10%, common ≥ 1% to < 10%, uncommon 0.1% to < 1%, rare
≥ 0.01% to < 0.1%, very rare <0.01% (includes isolated reports).
LAMISIL* tablets
In general LAMISIL* (terbinafine) is well tolerated. Side effects are usually mild to moderate in
severity and transient.
Clinical Trials Adverse Drug Reactions
LAMISIL* tablets
In clinical trials submitted for purposes of marketing approval in Canada adverse events occurred in
10.4% of patients receiving the recommended oral dose. Of these, 5% were mild to moderate
Tinea corporis, cruris 2-4 weeks * In patients with fingernail infections or toenail infections other than the big toe, or in younger patients, treatment
periods of less than 3 months may be adequate. In patients with infections of the big toenail, treatment for 3
months is usually sufficient, although some patients may require treatment for 6 months or longer. Poor nail
outgrowth during the first weeks of treatment may enable identification of those patients in whom longer therapy is
required. In onychomycosis the optimal clinical effect is seen some months after mycological cure and cessation of
treatment. This is related to the period required for outgrowth of healthy nail tissue.
** Complete resolution of the signs and symptoms may not occur until several weeks after mycolological cure.
TOPICAL
LAMISIL* cream
LAMISIL* cream can be applied once or twice daily depending on the indication. The affected areas
should be cleansed and dried thoroughly before application of LAMISIL*. The cream should be
applied to the affected skin and surrounding area in a thin layer and rubbed in lightly. In the case of
intertriginous infections (submammary, interdigital, intergluteal, inguinal) the area to which the cream
has been applied may be covered with a gauze strip, especially at night.
The duration and frequency of treatment varies with the indication and is dependent on the severity of
the infection:
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TABLE III Indication Duration of Treatment
Tinea pedis
Tinea corporis/cruris
Cutaneous Candidiasis
Pityriasis versicolor
1 week , once a day
1 week , once a day
1 to 2 weeks once or twice a day *
2 weeks, once or twice a day
* Two weeks of treatment with LAMISIL* cream produced slightly improved efficacy over treatment for one week.
The difference in outcome may not be clinically significant.
Many patients treated with shorter durations of therapy (1-2 weeks) continue to improve during the 2-
4 weeks after therapy has been completed. As a consequence, patients should not be considered
therapeutic failures until they have been observed for a period of 2-4 weeks after cessation of
treatment.
Relief of clinical symptoms usually occurs within a few days. Irregular use or premature
discontinuation of treatment increases the risk of recurrence. If there are no signs of improvement
after two weeks the diagnosis should be verified.
LAMISIL* spray
LAMISIL* spray is applied once or twice daily, depending on the indication. The affected areas
should be cleansed and dried thoroughly before application of LAMISIL*. A sufficient amount of
solution should be applied to wet the treatment area(s) thoroughly, and to cover the affected skin and
surrounding area (See WARNINGS AND PRECAUTIONS).
The duration of treatment varies with the indication and is dependent on the severity of the infection:
TABLE IV Indication Duration of Treatment
Tinea pedis
Tinea corporis/cruris
Pityriasis versicolor
1 week, once a day
1 week, once a day
1 week, twice a day
Relief of clinical symptoms usually occurs within a few days. Irregular use or premature
discontinuation of treatment increases the risk of recurrence. If there are no signs of improvement
after two weeks the diagnosis should be verified.
DOSING CONSIDERATIONS
Special populations:
Liver impairment
LAMISIL* tablets are not recommended for patients with chronic or active liver disease (see
Warnings and Precautions).
Page 18 of 51
Renal impairment
The use of LAMISIL* tablets has not been adequately studied in patients with renal impairment and is
therefore not recommended in this population (see Warnings and Precautions).
OVERDOSAGE
A few cases of overdosage with LAMISIL* tablets (up to 5 g) have been reported giving rise to
headache, nausea, epigastric pain and dizziness. The recommended treatment of overdosage consists
of eliminating the drug, primarily by the administration of activated charcoal and giving, symptomatic
supportive therapy, if needed.
No case of overdosage has been reported with LAMISIL* cream and spray. The low systemic
absorption of topical terbinafine renders overdosage extremely unlikely. Accidental ingestion of one
30 g tube of LAMISIL* cream or one 30 mL bottle of LAMISIL* spray, which contain 300 mg
terbinafine, is comparable to one LAMISIL* 250 mg tablet. However, should, larger amounts of
topical LAMISIL* be inadvertently ingested, adverse effects similar to those observed with an
overdosage of LAMISIL* tablets are to be expected (e.g. headache, nausea, epigastric pain and
dizziness). The alcohol content of the spray (28.8% v/v) has to be taken into account.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
LAMISIL* (terbinafine) is an allylamine which has a broad spectrum of antifungal activity. At low
concentrations LAMISIL* is fungicidal against dermatophytes, molds and certain dimorphic fungi. Its
activity against yeasts is fungicidal or fungistatic, depending on the species.
Pharmacodynamics
Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a
deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell
death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane. The enzyme
squalene epoxidase is not linked to the cytochrome P450 system.
When given orally, terbinafine accumulates rapidly in skin, hair and nails at levels associated with
fungicidal activity.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Page 19 of 51
Pharmacokinetics
Oral LAMISIL*
Absorption: Following oral administration, terbinafine is well absorbed (>70%) and the absolute
bioavailability of terbinafine from LAMISIL* tablets as a result of first-pass metabolism is
approximately 50 %. A single 250 mg dose of LAMISIL* tablets resulted in mean peak plasma
concentration of 1.3 g/ml within 1.5 hours after administration. At steady-state (70% steady state is
achieved in approximately 28 days), in comparison to a single dose, peak concentration of terbinafine
was on average 25% higher and plasma AUC increased by a factor of 2.3. From the increase in
plasma AUC an effective half-life of ~30 hours can be calculated. The bioavailability of terbinafine is
moderately affected by food (increase in the AUC of less than 20%), but not sufficiently to require
dosing adjustments.
Distribution: LAMISIL* binds strongly to plasma proteins (99%) and is lipophilic. LAMISIL* is
widely distributed in the body including adipose tissue. It rapidly diffuses through the dermis and
accumulates in lipophilic stratum corneum. It is also secreted in sebum, thus achieving high
concentrations in hair follicles, hair and sebum-rich skin. There is evidence that LAMISIL* is
distributed in the nail plate within the first few weeks of commencing therapy.
Metabolism and Excretion: Oral LAMISIL* is excreted mainly in urine (80%) and in feces (20%).
Following absorption terbinafine is metabolized rapidly and extensively by the liver. At least seven
cytochrome isoenzymes are involved in its metabolism with major contributions from CYP 2C9, CYP
1A2, CYP 3A4, CYP 2C8 and CYP 2C19. Biotransformation results in metabolites with no
antifungal activity which are excreted predominantly through the urine. No clinically relevant age-
dependent changes in steady-state plasma concentrations of terbinafine have been observed. Multiple
dose administration followed by extended blood sampling revealed a triphasic elimination with a
terminal half-life of approximately 16.5 days
Following a single 250 mg dose in 12 hepatically impaired cirrhotic (alcoholic) patients, total
clearance of terbinafine was reduced by about 40%. In a sample of 12 renally impaired patients
(median creatinine clearance of 17.6 mL/min), LAMISIL* clearance following a single 250 mg dose
was halved resulting in the doubling or more of peak plasma concentrations or AUC. Patients at the
highest and lowest ends of the renal impairment spectrum were not represented. There was no direct
correlation between creatinine clearance and terbinafine clearance in renally impaired patients, the
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metabolism of the drug having been impaired in these patients due to competition between metabolite
and parent drug.
Topical LAMISIL*
Less than 5% of the dose is absorbed after topical application to humans; systemic exposure is thus
very slight.
STORAGE AND STABILITY
Store at temperatures between 15 and 30C.
SPECIAL HANDLING INSTRUCTIONS
Protect tablets from light.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Tablets Cream Spray
Dosage Form 250 mg 1% cream 1% spray
Description Whitish to yellow tinged white, circular,
biconvex, with
bevelled edges tablet, scored on one side and
embossed "LAMISIL*
250"
White, smooth or almost smooth, glossy
cream with a weak
characteristic odor
Colourless to faintly yellow clear liquid
Composition Terbinafine 250 mg
(as terbinafine
hydrochloride); magnesium stearate,
hypromellose, silica
colloidal anhydrous, sodium starch
glycollate cellilose
microcrystalline granulate.
Terbinafine
hydrochloride 1%
w/w; benzyl alcohol; cetyl alcohol; cetyl
palmitate; isopropyl
myristate; polysorbate 60; purified water;
sodium hydroxide;
sorbitan monostearate; stearyl alcohol.
terbinafine hydro-
chloride 1% w/w; ceto-
macrogol 1000; ethanol (28.8% v/v); propylene
glycol; water.
Packaging Bottle of 100 and 500
tablets.
Blister packs of 28 tablets (14 tablets per
blister).
15 or 30 gram tubes 30 mL bottles
Page 21 of 51
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name: INN, BAN, USAN: terbinafine
Chemical Name: (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthaline-
methanamine (-hydrochloride)
Molecular
Formula/Mass:
Terbinafine base: 291.40
Terbinafine Hydrochloride: C21H26NCl/327.90
Structural formula:
Physicochemical
properties:
white to off-white finely crystalline powder
melting point: ~ 205°C.
pKa (I) value: 7.10
pH of a solution (0.5%) in methanol/water 4:6 (V/V): ~ 4.7. at
25°C.
Solubility: 0.63% (W/V) in water and >2% (W/V) in chloroform
Page 22 of 51
CLINICAL TRIALS
ORAL†
Onychomycosis
Two studies evaluated the efficacy of oral terbinafine in the treatment of toe or fingernail
onychomycosis.
Study Demographics and Trial Design
Summary of patient demographics for oral terbinafine clinical trials in onychomycosis
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender Race
SF1501 Randomized, double-
blind (double-dummy),
multicenter, parallel
group,stratified
enrolment
(toe/fingernail) b.i.d. vs
o.d. dosage
Terbinafine tablets, oral
125 mg b.i.d up to 48
wk (toenail) or 24 wk
(fingernail)
51 enrolled
43 evaluable
45
(18-74)
Male = 34
Female = 9
Not
reported
Terbinafine tablets,
2x125 mg o.d. up to 48
wk (toenail) or 24 wk
(fingernail)
52 enrolled
48 evaluable
45
(18-74)
Male = 34
Female =
14
Not
reported
SF00423 Randomized, double-
blind, multicenter,
parallel group,
griseofulvin-
comparative
Terbinafine capsules:
Oral, 250 mg bid for 3-6
months
47 enrolled
29 evaluable
44.6
(21-76 yr)
Male = 24
Caucasian
100%
Griseofulvin capsules:
Oral 250 mg bid for up
to 6 months (standard
treatment period is up to
12 months)
34 enrolled
22 evaluable
43.5
(20-61 yr)
Male = 15 Caucasian
100%
Study Results
Results of study SF1501 in onychomycosis
Primary Endpoints b.i.d.
Number (%) patients
o.d.
Number (%) patients
Mycological cure (negative KOH and culture) –
all infections
Toenails
25/31 (81%) 28/35 (80%)
Fingernails
10/10 (100%) 10/11 (91%)
Effective treatment (negative mycology plus
continuous or limited nail growth) at end of
treatment at week 24 - all infections
Toenails
24/32 (75%) 26/37 (70%)
Fingernails
10/11 (91%) 10/11 (91%)
Page 23 of 51
There were no significant differences between b.i.d and o.d. treatment regimens with respect to
mycological cure rates or rates of effective treatment. Mycological cure at end of treatment was 95 %
for fingernails and 80% for toenails. At follow-up visit 3-12 months later, over 81% of toenail
onychomycosis were cured without relapse.
Results of study SFO0423 in onychomycosis
Primary Endpoints Terbinafine
Number (%) patients
Comparator
Number (%) patients
Effective treatment (negative mycology plus
continuous or limited nail growth) at end of
treatment at week 24*
Toenail
11/20 (55%) 5/12 (42%)
Fingernail
7/9 (78%) 8/10 (80%)
Mycological cure (negative culture and KOH) at
week 24
Toenail
12/20 (60%) 5/12 (42%)
Fingernail
7/9 (78%) 7/10 (70%)
*The combined clinical/mycological endpoint was not specified in the protocol
Effective treatment in the LAMISIL* treated group was 78% fingernail and 55% toenail with
treatment durations of 3-6 months. Griseofulvin was 80% and 42% effective for fingernails and
toenails respectively. Thus, short duration therapy (3-6 months) using 500 mg per day of LAMISIL*
appears effective in many patients with onychomycosis due to dermatophyte infections.
Tinea corporis/cruris
Study demographics and trial design Summary of patient demographics for oral terbinafine clinical trials in tinea corporis/cruris
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race:
Percent
Caucasian
Placebo-
controlled:
SFO041B
5-OR
SFO041C
Randomized, single or
multicenter, parallel
group, double-blind,
placebo controlled
Terbinafine oral,
capsules, 125 mg bid
for 4 wk; 2 wk
follow-up
Entered 79
Evaluable 62
34 - 40 years
(18-74)
Male = 50
Female 11
71-100%
Matching placebo Entered 77
Evaluable 62
37-42
(18-70)
Male = 49
Female = 13
Griseofulvin-
controlled:
11-OR
SFO044
Randomized, single or
multicenter, parallel
group, double-blind,
double-dummy,
griseofulvin-controlled
Terbinafine oral
capsules, 125 mg and
placebo bid for up to
6 wk; 2-6 wk follow-
up
Entered 189
Evaluable 174
37-38
(17-69)
Male = 105
Female = 69
85-99%
Page 24 of 51
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race:
Percent
Caucasian
Griseofulvin oral
capsules 2x250 mg
bid for up to 6 wk; 2-
6 wk follow-up
Entered 192
Evaluable 170
31-34
(17-85)
Male = 107
Female = 63
Ketoconazole
controlled:
SF3006
SF0047
Randomized, single or
multicenter, parallel
group, double-blind,
double-dummy,
griseofulvin-controlled
Terbinafine oral
capsules, 125 mg and
placebo bid for up to
6 wk; 4-8 wk follow-
up
Entered 73
Evaluable 65
34-48
(18-80)
Male = 40
Female = 25
60-92%
Ketoconazole oral
capsules 200 mg od
(placebo od) for up to
6 wk; 2-6 wk follow-
up
Entered = 71
Evaluable = 62
31-43
(16-70)
Male = 40
Female = 22
Study results
Combined results of placebo-controlled studies SF 0041 B, 5-OR, SF 0041C in tinea corporis/cruris
1
Primary Endpoints Terbinafine
Number (%)
Placebo
Number (%)
Mycological cure (negative culture and KOH)
at follow-up
7-30 (100 - 64%) 0-4 (0-36%)
Effective treatment (mycological cure and no
to minimal signs or symptoms) at follow-up
8-30 (62-91%) 0-4 (0-23%)
5-OR: mycological cure results (combined culture and KOH results) were not provided and too few patients returned at follow-up for meaningful assessments. However, at end of treatment, terbinafine was significantly better than placebo in terms of mycological cures and negative KOH results (Negative KOH of 73% vs 17% for active and placebo, p = 0.043; Negative cultures of 73% vs 0% for active and placebo, p = -.007) .
SF 0041B: too few placebo patients returned at follow-up for meaningful assessments; however, at end of therapy the proportion of patients with mycological cures was greater in the terbinafine group compared with placebo; effective treatment was noted in 75% and 23% of active and placebo groups
1 Range of values represents the highest and lowest values noted across the studies represented
The efficacy of a up to 6 weeks of treatment with terbinafine was consistently positive across 3
placebo-controlled trials both in rates of mycological cures and in the combination of mycological and
clinical endpoints. In the placebo-controlled trials, placebo patients often did not return at the post-
treatment follow-up to provide meaningful results at that visit. However, results at the end of
treatment speak to the high degree of efficacy of terbinafine using clinical and/or mycological
endpoints. Results of 4 studies with active comparators show terbinafine to be at least as good as, if
not better than, systemically administered griseofulvin and ketoconazole.
Results of griseofulvin-controlled studies 11-OR and SF 0044 in tinea corporis/cruris
1
Primary Endpoints Terbinafine
Number (%)
Comparator
Number (%)
Mycological cure (negative culture and
KOH) at follow-up
111 - 40 (93-100%) 101- 36 (94 – 95%)
Page 25 of 51
Primary Endpoints Terbinafine
Number (%)
Comparator
Number (%)
Effective treatment (mycological cure and
no to minimal signs or symptoms) at
follow-up
119 – 37 (94 – 77%) 108 – 36 (86-82%)
1 Range of values represents the highest and lowest values noted across the studies represented
Results of ketoconazole-controlled studies SF 3006 and SF 0047 in tinea corporis/cruris
1
Primary Endpoints Terbinafine
Number (%)
Comparator
Number (%)
Mycological cure (negative culture and
KOH) at follow-up
28-36 (100 – 97%) 23 – 31 (92-86)
Effective treatment (mycological cure
and no to minimal signs or symptoms) at
follow-up
28 – 35 (100 – 95%) 23 – 29 (92 – 78 %)
1 Range of values represents the highest and lowest values noted across the studies represented
Tinea Pedis
Study demographics and trial design
Summary of patient demographics for clinical trials in tinea pedis
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender Race
39-40OR Randomized, double-
blind, multicenter,
placebo-controlled
Terbinafine tablets
(or matching
placebo) 125 mg bid
for 6 weeks; 2 week
follow-up
Terbinafine
Enrolled 26
Evaluable 23
37 years
(20-64)
Male = 15
Female =8 92%
Caucasian
Placebo
Enrolled 24
Evaluable 18
40 years
(20-68)
Male = 13
Female=5
SF 0508 Randomized, double-
blind, multicenter,
placebo-controlled
Terbinafine tablets
(or matching
placebo) 125x2 mg
od for 2 weeks; 6
week follow-up
Terbinafine
Enrolled 18
Evaluable 14
39 years
(19-72)
Male = 20
Female =6
79%
Caucasian
Placebo
Enrolled 19
Evaluable 14
45 years
(20-82)
Male =23
Female = 4
SF 0025 Randomized, double-
blind, multicenter,
griseofulvin controlled
Terbinafine
capsules, 125 mg
bid for 6 wk; 2 wk
follow-up
Enrolled 39
Evaluable 33
38 years
(18-79)
Male = 17
Female = 16 95%
Caucasian
Griseofulvin
capsules 250 mg bid
for 6 wk; 2 wk
follow-up
Enrolled 37
Evaluable 33
35 years
(14-59)
Male = 18
Female = 15
20-OR Randomized, double-
blind, multicenter,
griseofulvin controlled
Terbinafine
capsules, 125 mg
bid for 6 wk; 2 wk
follow-up
Enrolled 18
Evaluable 16
38 years
(22-63)
Male = 11
Female = 5 82%
Caucasian
Page 26 of 51
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender Race
Griseofulvin
capsules 250 mg bid
for 6 wk; 2 wk
follow-up
Enrolled 18
Evaluable 12
36 years
(20-49)
Male = 9
Female = 3
Study results Results of placebo controlled studies 39-40OR, SFO508 in tinea pedis
Primary Endpoints Terbinafine
Number (%)
Placebo
Number (%)
Mycological cure (negative culture and microscopy)
at follow-up
Study 39-40OR* 17/22 (77%) 0/6 (0%)
Study SF0508† 12/14 (86)% 1/14(7%)
Effective treatment (negative mycology and minimal
signs and symptoms) at follow-up
Study 39-40OR* 15/23 (65%) 0/18 (0%)
Study SF0508† 10/14 (71%) 0/14 (0%)
* Too few placebo patients at follow-up to determine † P <0.001, Fisher Exact test, one-sided
Placebo-controlled trials demonstrated a consistent treatment effect 2-6 weeks after cessation of
treatment, whether assessed solely by mycological results, or when assessed by combined
mycological and clinical parameters. Both 6-week and 2-week, o.d., and b.i.d. regimens were
effective. In study 39-40OR, too few placebo patients returned at the follow-up visit to allow
meaningful statistical analysis of results. Mycological cures and effective treatment rates at end of the
6 week treatment period, however, were significantly greater in the terbinafine treatment group than in
the placebo group.
Results of study griseofulvin-controlled studies SF 0025 and 20-OR in tinea pedis
Primary Endpoints Terbinafine
Number (%)
Comparator
Number (%)
Mycological cure (negative culture and
microscopy) at follow-up
SF 0025* 32/33 (97%) 28/31 (90%)
20-OR* 16/16 (100%) 6/11 (55%)
Effective treatment (negative mycology and
minimal signs and symptoms) at follow-up
SF 0025† 32/33 (97%) 26/33 (79%)
20-OR† 14/16 (88%) 5/11 (45%)
* Statistical significance not reported † p = 0.054 Fishers Exact test
Page 27 of 51
Two weeks after the end of 6 week courses of treatment, two small studies showed terbinafine to be
better than griseofulvin in terms of mycological or combined mycological and clinical parameters.
†LAMISIL* 125 mg tablets are not currently available on the Canadian market.
TOPICAL - LAMISIL* Cream
Tinea corporis/Tinea cruris
Study demographics and trial design Summary of patient demographics for terbinafine cream clinical trials in tinea corporis/cruris
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age across
studies (Range)
Gender Race:
Percent
Caucasian
Placebo-
controlled:
SF 2002
SF 2004
Randomized,
multicenter, parallel
group, double-blind,
placebo controlled
Terbinafine 1%
cream once daily for
1 wk; 3 wk follow-
up
Cream vehicle
Entered 78
Evaluable 66
31-39
(5-89)1
Male 271
Female 91
Causcasian
51-67%
Entered 82
Evaluable 73
36-40
(6-70) 1
Male 311
Female 71
1 Range and distribution by sex provided only for SF 2002.
Study results
Combined results of placebo-controlled studies SF 2002 and SF2004, terbinafine cream 1%, in tinea corporis
/cruris, 2 wk post-treatment
Primary Endpoints Terbinafine
Number (%)
Placebo
Number (%)
Mycological cure (negative culture and KOH) at
follow-up*
30-27
(88-93%)
5 in each study
(31% in each study)
Effective treatment (mycological cure and no to
minimal signs or symptoms) at follow-up†
26-29
(81-87%)
4-5
(11-14%)
*Study 2002, p value for mycological cure not provided; p <0.007 for KOH and culture results individually. For study 2004 p <0.001
for mycological cure † p <0.001 for both studies
Two double-blind, placebo controlled studies evaluated whether one week of LAMISIL* 1% cream
was sufficient to treat Tinea corporis/cruris. At the three week follow-up LAMISIL* was effective in
81% -87% of patients, clearly demonstrating the efficacy of daily short duration (one week) treatment.
Page 28 of 51
Tinea Pedis
Study demographics and trial design
Summary of patient demographics for terbinafine 1% cream clinical trials in tinea pedis
Study # Trial design Dosage, route of
administration
and duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race:
Percent
Caucasian
Placebo-
controlled:
81 T, 4 wk
SF0505, 2 wk
SF0020, 4 wk
Randomized single or
multicenter, parallel
group, double-blind,
placebo controlled
Terbinafine 1%
cream once daily
for 2-4 wk
Entered 90
Evaluable 70
36-37 yr
(12-72)
Male 38
Female 32
Race not
quantified;
majority
were
Mestizo Cream vehicle Entered 87
Evaluable 70
38-41 yr
(10-86)
Male 39
Female 31
Clotrimazole-
controlled:
SF018
Randomized, single or
multicenter, parallel
group, double-blind,
clotrimazole-crean
controlled
Terbinafine 1%
cream once daily
for 4 wk; 2 wk
follow-up
Entered 164
Evaluable 133
40 yr
(18-76)
Male 100
Female 33
Caucasian
79%
Clotrimazole 1%
cream once daily
for 4 wk; 2 wk
follow-up
Entered 168
Evaluable 134
40 yr
(15-88)
Male 94
Female 39
Ketoconazole
controlled
ITUK 85
Randomized, single or
multicenter, parallel
group, ketoconazole-
cream controlled
Terbinafine 1%
cream once daily
for 4 wk; 2 wk
follow-up
Entered 89
Evaluable 72
38
(17-61)
Male 72
Female 0
Caucasian
96%
Ketoconazole 2%
cream once daily
for 4 wk; 2 wk
follow-up
Entered 89
Evaluable 73
37
(17-63)
Male 73
Female 0
Study results
Combined results of placebo-controlled studies terbinafine 1% cream studies in tinea pedis1
Primary Endpoints Terbinafine
Number (%)
Placebo
Number (%)
Significance
Mycological cure (negative culture
and KOH) at follow-up
10-24
(67-95)
1-13
(13-60%)
Not specified for 81 T
P <0.03 for others
Effective treatment (mycological
cure and no to minimal signs or
symptoms) at follow-up
9-23
(60-80%)
1-12
(7-33%)
Not specified for 81 T
P <0.006 for others
1 Range of values represents the highest and lowest values noted across the studies represented.
Combined results of active-controlled studies terbinafine 1% cream studies in tinea pedis
Primary Endpoints Terbinafine
Number (%)
Active control
Number (%)
Mycological cure (negative culture and KOH) at follow-up:
Page 29 of 51
Vs clotrimazole cream 116
(91%)
98
(78%)
Vs ketoconazole cream 68
(100%)
66
(96%)
Effective treatment (mycological cure and no to minimal signs or symptoms) at follow-up:
Vs clotrimazole cream 98
(75%)
79
(61)
Vs ketoconazole 61
(86%)
58
(81%)
Effective treatment at follow-up is estimated from relapse data (0 relapse for terbinafine; 2 relapses for ketoconazole)
Cutaneous Candidiasis
Study demographics and trial design Summary of patient demographics for terbinafine 1% cream clinical trials in cutaneous candidiasis
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race: Percent
Caucasian
SF 1003
SF 1004
Randomized, double-
blind, single-center,
vehicle controlled
Terbinafine 1%
cream, once daily
for 1 wk; 3 wk
follow-up
Entered 69
Evaluable 63
35-40
(6 to 78)
Male 31
Female 32
Black or
Mestiza and
Caucasian
Terbinafine 1%
cream vehicle , once
daily for 1 wk; 3 wk
follow-up
Entered 67
Evaluable 63
34-37
(13-81)
Male 44
Female 19
Study results
Combined results of vehicle-controlled studies terbinafine 1% cream studies in cutaneous candidiasis
Primary Endpoints Terbinafine
Number (%)
Placebo
Number (%)
Significance
Mycological cure (negative culture
and KOH) at follow-up
22-25
(86-73%)
9-11
(28-61%)
NS
Effective treatment (mycological cure
and no to minimal signs or
symptoms) at follow-up
22-23
(71-72%)
1-7
(3-23%)
P <0.001 in both studies
p-values and results for effective treatment at follow-up are based on ITT population
The efficacy of one week of once-daily treatment with terbinafine 1% cream in cutaneous candidiasis
is shown by the significantly greater rate of combined mycological and clinical outcomes, even 3
weeks post-treatment. While mycological cures were not significantly different between treatment
groups post-treatment, they were significantly different at the end of treatment. Even though
mycological cure appeared to decrease post-treatment, the rates of clinical cure (negative mycology
and minimal signs and/or symptoms) increased. In study SF1003, complete clinical cure was noted
for 3 terbinafine patients at end of treatment and 15 at Week 4. In study SF1004 for the terbinafine
group, there was 1 complete cure at end of treatment but 17 at Week 4. No such increase in complete
cures was noted in the vehicle group.
Page 30 of 51
TOPICAL - LAMISIL* Spray
Tinea corporis/Tinea cruris
Study demographics and trial design Summary of patient demographics for terbinafine 1% spray clinical trials in tinea corporis/cruris
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race:
Percent
Caucasian
SFF 303
Randomized, double-
blind, vehicle
controlled (2:1
terbinafine: vehicle),
parallel group,
multicenter
Terbinafine 1%
solution once daily
for 7 days; 7 wk
follow-up
Entered 102
ITT 72
42
(17-84)
Male 56
Female 16
89%
Terbinafine solution
vehicle as above
Entered 49
ITT 37
45
(18-71)
Male 28
Female 9
86%
SFF 105 Randomized, double-
blind, vehicle
controlled, parallel
group, multicenter
Terbinafine 1%
solution once daily
for 7 days; 3 wk
follow-up
Entered 32
ITT 26
41
(9-82)
Male 17
Female 9
81%
Terbinafine solution
vehicle as above
Entered 34
ITT 26
43
(6-71)
Male 18
Female 8
77%
SFF 108 Randomized, double-
blind, vehicle
controlled, parallel
group, multicenter
Terbinafine 1%
solution once daily
for 7 days; 3 wk
follow-up
Entered 36
ITT 35
32
(5-76)
Male 26
Female 9
71%
Terbinafine solution
vehicle as above
Entered 36
ITT 35
37
(8-81)
Male 23
Female 12
71%
Study results
LAMISIL* 1% topical solution was significantly more effective than placebo when applied once
daily for one week in patients with Tinea corporis/cruris.
Number (%) subjects with effective treatment (ET) or with both negative microscopy and culture (NM) at study
end-point
Study No. Treatment Results
ET NM
SFF 303 LAMISIL*
Placebo
71%
11%
p<0.001
85%
28%
p<0.001
SFF 105 LAMISIL*
Placebo
65%
8%
p<0.001
69%
23%
p=0.004
LAMISIL* 65% 76%
Page 31 of 51
Placebo 20%
p<0.001
29%
p<0.001
Tinea pedis
Study demographics and trial design Summary of patient demographics for terbinafine 1% spray clinical trials in Tinea Pedis
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race:
Percent
Caucasian
SFF 301 Multicenter, double-
blind, vehicle-
controlled, 2:1
randomization
(terbinafine:vehicle)
Terbinafine 1%
solution once daily
for 7 days; 7 wk
follow-up
Entered 115
ITT 105
41
(18-81)
Male 51
Female 20
96%
Terbinafine solution
vehicle as above
Entered 57
ITT 51
42
(18-75)
Male 35
Female 4
95%
SFF 351 Multicenter, double-
blind, vehicle-
controlled, 2:1
randomization
(terbinafine:vehicle)
Terbinafine 1%
solution twice daily
for 7 days; 7 wk
follow-up
Entered 104
ITT 81
41
(12-83)
Male 47
Female 11
60%
Terbinafine solution
vehicle as above
Entered 49
ITT 38
43
(25-72)
Male 18
Female 10
82%
Study 309 Multicenter, double-
blind, double-dummy,
randomized (1:1)
clotrimazole-
controlled
Terbinafine 1%
solution twice daily
for 7 days; vehicle 3
wk; 4 wk follow-up
Entered 348
ITT 311
47
(13-84)
Male 150
Female 67
98%
Clotrimazole XXX
twice daily for 4 wk;
4 wk follow-up
Entered 351
ITT 323
45
(12-85)
Male 147
Female 65
97%
Study Results
Whether applied once or twice daily for one week or once daily for two weeks, LAMISIL 1% topical
solution was significantly more effective than placebo in the treatment of Tinea pedis but was
comparable to cotrimazole.
Number (%) subjects with effective treatment (ET) or with both negative microscopy and culture (NM) at end of
study
Study No. Treatment Treatment regimen Results
ET NM
SFF 351 LAMISIL*
Placebo
1 week, b.i.d. 66%
4%
p<0.001
88%
14%
p<0.001
SFF 301 LAMISIL*
Placebo
1 week o.d. 76%
21%
p<0.001
85%
23%
p<0.001
Page 32 of 51
SFF 309 LAMISIL*
Cotrimazole
1 week, b.i.d. 83%
82%
p=0.649
92%
91%
p=0.411
Tinea versicolor
Study demographics and trial design Summary of patient demographics for terbinafine 1% spray clinical trials in tinea versicolor
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
across studies
(Range)
Gender Race:
Percent
Caucasian
SFF 305 Randomized,
multicenter, double-
blind, vehicle-
controlled (2:1
terbinafine:vehicle)
Terbinafine 1%
solution twice daily
for 7 days; 7 wk
follow-up
Entered 79
ITT 76
34
(16-68)
Male 39
Female 37
89%
Terbinafine solution
vehicle twice daily
for 7 days; 7 wk
follow-up
Entered 36
ITT 34
32
(15-72)
Male 20
Female 14
91%
SFF 353 Randomized,
multicenter, double-
blind, vehicle-
controlled (2:1
terbinafine:vehicle)
Terbinafine 1%
solution twice daily
for 7 days; 7 wk
follow-up
Entered 109
ITT 97
34
(14-67)
Male 47
Female 50
84%
Terbinafine solution
vehicle twice daily
for 7 days; 7 wk
follow-up
Entered 49
ITT 47
34
(14-59)
Male 26
Female 21
81%
Study Results
When compared to placebo treatment, a one week twice daily application of LAMISIL* 1% solution
spray was significantly more effective in the treatment of Pityriasis versicolor. Treatment was
effective in 70% of LAMISIL* treated patients compared to 32% patients who used placebo
(p<0.001). At the end of the study there was also a significant difference between the numbers of
patients with negative microscopy, who had received LAMISIL* treatment (79%) compared to the
placebo treated (44%) [p<0.001].
Number (%) subjects with effective treatment (ET – primary variable
1) or negative
microscopy (NM) at end of study
Study Treatment Number of patients
(%)
ET NM
SFF 305 LAMISIL*
Placebo
52 (70%)
11(32%)
p<0.001
58 (79%)
15 (44%)
p<0.001
SFF 353 LAMISIL*
Placebo
75 (77%)
13 (28%)
p<0.001
76 (78%)
14 (30%)
p<0.001
1Effective treatment is defined as negative microscopy and a total sign/symptom score of 0 or 1.
Page 33 of 51
DETAILED PHARMACOLOGY
The mechanism of action of terbinafine involves specific inhibition of fungal ergosterol biosynthesis
at the point of squalene epoxidation, leading to a deficiency of an essential component of the fungal
cell membranes (i.e. ergosterol) and to intracellular accumulation of the precursor squalene. The latter
effect appears to be responsible for the primary fungicidal activity, its consequent disruption of cell
membranes and cell wall synthesis having been noted in ultrastructural studies of terbinafine treated
fungi. This mechanism distinguishes terbinafine from the azole antimycotics, which affect a later step
in ergosterol biosynthesis by inhibiting 14 -demethylase, a cytochrome P-450 enzyme upon which
terbinafine has no effect. In contrast to many azoles, terbinafine does not bind to cytochromes P-450
in mammalian steroidogenic tissues.
Oral
The pharmacokinetics of orally administered terbinafine in plasma can best be described by a
2-compartment model. More than 80% of the dose is absorbed, clearance of the drug is high, it is
extensively metabolized in the liver, and it is extensively distributed in the tissues. The peak plasma
concentration is proportional to the dose, and the time to peak is ~ 2 hours, independent of the dose.
Mean concentrations of terbinafine (in µg/g) measured in the stratum corneum, dermis/epidermis,
hair, sweat, and sebum during and after 12 days of 250 mg LAMISIL* per day in 10 healthy
volunteers were as follows before (day 0), during (days 2, 6, 12) and after treatment (days 13 and 16).
Day 0 2 6 12 13 16
Stratum corneum 0.11 0.86 2.84 9.05 5.08 3.06
Derm / epiderm 0 0.05 0.23 0.35 0.11 0.14
Sebum 0 38.2 43.1 39.7 45.1 18.8
Hair 0.02 0.24 1.30 2.60 2.11 1.35
Sweat 0 0 0 0 0 0
The pattern of tissue distribution suggests a rapid diffusion of drug through the dermis/lower
epidermis into the stratum corneum, where maximal concentrations were achieved at day 12, and the
t1/2 was 3-4 days (this implies that the concentrations of terbinafine would remain above the MIC for
most dermatophytes for 3 weeks). Another route of terbinafine distribution likely to be important for
the treatment of dermatomycosis would be secretion into sebum, in which drug levels were high and
persisted for several days after cessation of treatment.
Page 34 of 51
In a study evaluating the efficacy of terbinafine in the treatment of onychomycosis, plasma levels
were measured monthly in 9 patients, half of whom received 250 mg terbinafine q.d. in the evening
and the other half 125 mg b.i.d. A pharmacokinetic steady state was attained at or before 4 weeks, the
first analysis time point available. The steady-state plasma concentrations were 0.22 - 0.56 and 0.15 -
0.35 µg/ml for the b.i.d. and q.d. doses, respectively, and did not increase over time.
Topical
Pharmacokinetic studies in humans revealed that absorption of terbinafine cream or spray through
skin is less than 5%. In a single dose study of 14
C-terbinafine, urinary excretion accounted for ~ 90%
of the absorbed dose, and the highest concentration appeared in the urine 2 and 3 days after
terbinafine application.
Microbiology
In vitro
The minimum inhibitory concentrations (MICs) of terbinafine were determined by serial dilution tests
against yeasts, molds, dermatophytes, the mycelial form of Candida albicans, Pityrosporum spp., and
Sporothrix schenkil. The spectrum and MIC values obtained for the various species and strains of
fungi at different research laboratories (summarized as a range of activity in the following table)
demonstrate that terbinafine possesses a high activity against dermatophytes, aspergilli, and
dimorphous or dermatiaceous fungi. The susceptibility of blastospores of various species and strains
of yeasts to terbinafine is much lower with MIC's ranging from 0.1 to > 128 μg/ml. The efficacy of
terbinafine against 2 clinically important yeasts was confirmed by an evaluation of the susceptibility
of 78 clinical isolates of Candida albicans and 20 of Candida parapsilosis. Blastophores of the
Candida parapsilosis were more sensitive than those of Candida albicans, but the mycelial growth
form of the Candida albicans (considered the pathogenic form) was the most sensitive form (MIC 50
= 0.195 µg/mL).
Summary of results published on in vitro activities of terbinafine against pathogenic and
opportunistic fungi Fungus MIC range (µg/mL)
I. Dermatophytic Fungi Trichophyton mentagrophytes
rubrum
rubrum verrucosum
Epidermophyton floccosum
Microsporum canis
Microsporum gypseum
Microsporum persicolor
0.001-0.01
0.001- 0.01
0.001- 0.006
0.001-<0.06
0.005-0.01
0.005-0.01
0.002-0.003
Page 35 of 51
II. Filamentous Fungi Aspergillus spp.
Aspergillus flavus
Aspergillus fumigatus
Aspergillus niger
Aspergillus terreus
Pseudallescheria boydii
Mucor, Rhizopus spp.
Acremonium spp.
Curcularia fallax
Fusarium spp.
Hendersonula toruloidea
Lasiodiplodia theobromae
Paecilomycea spp.
Scopulariopsis brevicaulis
Scytalidium hyalinum
0.005-5.0
0.01-0.5
0.02-5.0
0.005-0.5
0.05-5.0
32.00->64.0
64.0->128.00
1.0-4.0
0.25-0.5
32.0->64.0
1.0-4.0
0.25-0.5
8.0-64.0
0.5-8.8
1.0-4.0
III. Dimorphic Fungi Blastomyces dermatitidis
Histoplasma capsulatum
Sporothrix schenckii
-0.39
-0.2
-2.0
IV. Pathogenic Yeasts Candida albicans (yeast form)